Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer
Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy or vascular-targeted photodynamic therapy with radiotherapy fractions used to treat prostate cancer. Firstly, the aim of this study was to investigate the tum...
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| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1826308060511993856 |
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| author | Philippou, Y |
| author2 | Bryant, R |
| author_facet | Bryant, R Philippou, Y |
| author_sort | Philippou, Y |
| collection | OXFORD |
| description | Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy or vascular-targeted photodynamic therapy with radiotherapy fractions used to treat prostate cancer. Firstly, the aim of this study was to investigate the tumour immune microenvironment and tumour vascular responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, the effects of combining fractionated radiotherapy with anti-PD-L1 immune checkpoint blockade or vascular-targeted photodynamic therapy on tumour growth delay was investigated. 3 x 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post 3 x 5Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 x 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Fractionated radiotherapy induced 'vascular normalisation' changes in prostate cancer flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. Fractionated radiotherapy followed by vascular-targeted photodynamic therapy significantly delayed tumour growth in flank prostate cancer allograft pre-clinical models, compared with monotherapy with fractionated radiotherapy or vascular-targeted photodynamic therapy, and improved overall survival. This research suggests that multi-modal therapies for prostate cancer beyond immunotherapy may be necessary to achieve radiotherapy-induced anti-tumour responses. Combining fractionated radiotherapy with vascular-targeted photodynamic therapy may be a promising multimodal approach in prostate cancer therapy. This research provides proof-of-concept for this multimodality treatment to inform early phase clinical trials. |
| first_indexed | 2024-03-07T07:12:23Z |
| format | Thesis |
| id | oxford-uuid:7eed35aa-2a70-40b1-a8c1-6695d145e195 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:12:23Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:7eed35aa-2a70-40b1-a8c1-6695d145e1952022-07-07T15:11:09ZInvestigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancerThesishttp://purl.org/coar/resource_type/c_db06uuid:7eed35aa-2a70-40b1-a8c1-6695d145e195TRAMP miceProstate--Cancer--Research--United States--Financevascular-targeted photodynamic therapyRadiotherapyMagnetic resonance imagingGene expression analysisFlow cytometryEnglishHyrax Deposit2021Philippou, YBryant, RMills, IMuschel, RRadiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy or vascular-targeted photodynamic therapy with radiotherapy fractions used to treat prostate cancer. Firstly, the aim of this study was to investigate the tumour immune microenvironment and tumour vascular responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, the effects of combining fractionated radiotherapy with anti-PD-L1 immune checkpoint blockade or vascular-targeted photodynamic therapy on tumour growth delay was investigated. 3 x 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post 3 x 5Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 x 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Fractionated radiotherapy induced 'vascular normalisation' changes in prostate cancer flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. Fractionated radiotherapy followed by vascular-targeted photodynamic therapy significantly delayed tumour growth in flank prostate cancer allograft pre-clinical models, compared with monotherapy with fractionated radiotherapy or vascular-targeted photodynamic therapy, and improved overall survival. This research suggests that multi-modal therapies for prostate cancer beyond immunotherapy may be necessary to achieve radiotherapy-induced anti-tumour responses. Combining fractionated radiotherapy with vascular-targeted photodynamic therapy may be a promising multimodal approach in prostate cancer therapy. This research provides proof-of-concept for this multimodality treatment to inform early phase clinical trials. |
| spellingShingle | TRAMP mice Prostate--Cancer--Research--United States--Finance vascular-targeted photodynamic therapy Radiotherapy Magnetic resonance imaging Gene expression analysis Flow cytometry Philippou, Y Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title | Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title_full | Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title_fullStr | Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title_full_unstemmed | Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title_short | Investigating multi-modal therapy with radiotherapy, vascular-targeted photodynamic therapy and immunotherapy in pre-clinical models of prostate cancer |
| title_sort | investigating multi modal therapy with radiotherapy vascular targeted photodynamic therapy and immunotherapy in pre clinical models of prostate cancer |
| topic | TRAMP mice Prostate--Cancer--Research--United States--Finance vascular-targeted photodynamic therapy Radiotherapy Magnetic resonance imaging Gene expression analysis Flow cytometry |
| work_keys_str_mv | AT philippouy investigatingmultimodaltherapywithradiotherapyvasculartargetedphotodynamictherapyandimmunotherapyinpreclinicalmodelsofprostatecancer |